Novel Associations between Related Proteins and Cellular Effects of High-Density Lipoprotein

BACKGROUND AND OBJECTIVES: Recent studies have examined the structure-function relationship of high-density lipoprotein (HDL). This study aimed to identify and rank HDL-associated proteins involved in several biological function of HDL. METHODS: HDLs isolated from 48 participants were analyzed. Cholesterol efflux capacity, effect of HDL on nitric oxide production, and vascular cell adhesion molecule-1 expression were assessed. The relative abundance of identified proteins in the highest vs. lowest quartile was expressed using the normalized spectral abundance factor ratio. RESULTS: After adjustment by multiple testing, six proteins, thyroxine-binding globulin, alpha-1B-glycoprotein, plasma serine protease inhibitor, vitronectin, angiotensinogen, and serum amyloid A-4, were more abundant (relative abundance ratio ≥2) in HDLs with the highest cholesterol efflux capacity. In contrast, three proteins, complement C4-A, alpha-2-macroglobulin, and immunoglobulin mu chain C region, were less abundant (relative abundance ratio <0.5). In terms of nitric oxide production and vascular cell adhesion molecule-1 expression, no proteins showed abundance ratios ≥2 or <0.5 after adjustment. Proteins correlated with the functional parameters of HDL belonged to diverse biological categories. CONCLUSIONS: In summary, this study ranked proteins showing higher or lower abundance in HDLs with high functional capacities and newly identified multiple proteins linked to cholesterol efflux capacity.ope

Association between localised retinal nerve fibre layer defects and cardiovascular risk factors

Localised retinal nerve fibre layer defects (RNFLDs) are reported to indicate the degree of glaucomatous damage but can also be sequelae of retinal vascular insufficiency as a result of systemic vascular factors. We investigated the association between RNFLDs and cardiovascular risk factors. RNFLDs were detected in 440 (29.2%) of 1508 subjects. The presence of RNFLDs was associated with higher HbA1c (odds ratio [OR] 1.289, p < 0.001), higher 24-h mean systolic blood pressure (SBP; OR 1.013, p < 0.005), and lower estimated glomerular filtration rate (eGFR; OR 0.995, p < 0.005). An increasing number of RNFLDs was correlated with higher SBP (r = 0.186, p < 0.001), higher HbA1c (r = 0.128, p < 0.010), lower eGFR (r = -0.112, p < 0.020), and younger age (r = -0.303, p < 0.001). Subjects with RNFLDs had a higher predicted 10-year risk of atherosclerotic cardiovascular disease than did those without RNFLDs (9.7% vs 7.9%, p = 0.008 in middle-aged subjects, 25.6% vs 23.2%, p = 0.040 in older subjects). In conclusion, RNFLDs are associated with SBP, eGFR, and HbA1c. Concomitant cardiovascular risk factors should be considered when evaluating patients with localised RNFLDs.ope

The Role of Carotid Ultrasound for Cardiovascular Risk Stratification beyond Traditional Risk Factors

Primary prevention and early detection of cardiovascular disease is important, as it is the leading cause of death throughout world. Risk stratification algorithms, such as Framingham Risk Score and European Systematic Coronary Risk Evaluation, that utilize a combination of various traditional risk factors have been developed to improve primary prevention. However, the accuracy of these algorithms for screening high risk patients is moderate at best. Accordingly, the use of biomarkers or imaging studies may improve risk stratification. Carotid ultrasound, which measures both carotid intima-media thichkness (cIMT) and carotid plaque, is useful in detecting the degree of subclinical carotid atherosclerosis, and has the advantage of being noninvasive and safe. Several large epidemiologic studies have indicated that cIMT and carotid plaque are closely related with other cardiovascular risk factors and may be useful for risk reclassification in subjects deemed to be at intermediate risk by traditional risk scores. Moreover, recent clinical guidelines for management of hypertension or dyslipidemia highlight the usefulness of cIMT in high risk patients. In this article, we review evidence for the usefulness of measurement of cIMT and carotid plaque for cardiovascular risk stratification.ope

마이크로RNA에 의한 PCSK9 및 콜레스테롤 항상성 조절

Dept. of Medical Science/박사Low density lipoprotein (LDL) receptor on the cellular membrane is a receptor responsible for uptake of serum LDL-cholesterol into the cell. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the LDL receptor (LDLR), followed by internalization of the complex and degradation of LDLR, and ultimately regulates cholesterol homeostasis. Transcription of PCSK9 is regulated by SREBP (sterol regulatory element binding protein) but regulation by microRNA (miRNA) is still not known. The purpose of this study is to show the existence of miRNA regulating PCSK9 and involving cholesterol homeostasis. In order to discover the posttranscriptional regulation mechanism of PCSK9, bioinformatic algorithms were utilized to discover miRNAs expected to target PCSK9. Overexpression of these miRNAs reduced both PCSK9 mRNA and protein significantly whereas increased LDLR protein. 3？UTR (untranslated region) luciferase reporter assay showed that these miRNAs downregulated PCSK9 expression by binding 3？UTR of PCSK9. Site-directed mutagenesis of predicted seed region in PCSK9 mRNA revealed specific interaction between miRNAs and PCSK9 mRNA. In Dil-LDL uptake assay, overexpression of these miRNA demonstrated a relative increase in Dil-LDL uptake by 70% or greater. In addition, it was indentified that miR-224 regulated the inducible degrader of the LDL receptor (IDOL) by 3？UTR reporter assay. These indicate that miRNAs may be yet another mechanism involved in cholesterol homeostasis by posttranscriptional regulation of PCSK9 or IDOL and that utilization of miRNA may be a method of treatment of hypercholesterolemia.ope

Temporal trends in heart failure over 11 years in the aging Korean population: A retrospective study using the national health insurance database

Background: Understanding national trends of heart failure (HF) is crucial for establishing prevention and treatment strategies. We aimed to investigate the 11-year trends of HF in the South Korean population. Methods: Using the Korean National Health Insurance Service database, we identified 3,446,256 patients with HF between 2004 and 2014. Results: The prevalence of HF was 1.42% in 2004, steadily increasing to 1.98% in 2014. However, the age-adjusted prevalence of HF remained stable (1.43% in 2014). The incidence of HF was 6.1/1000 person-years in 2004 and remained at similar levels, reaching 5.4/1000 person-years in 2014. The age-adjusted incidence of HF slowly decreased to 3.94/1000 person-years in 2014. The event rate for hospitalized patients with HF remained stable increasing from 1.40 in 2004 to 1.87/1000 person-years in 2014, and the age-adjusted event rate of hospitalized HF decreased to 1.22 in 2014. Conclusions: In South Korea, between 2004 and 2014, the prevalence of HF increased while the incidence of HF remained stable. Furthermore, the age-adjusted HF prevalence was stable, and the age-adjusted incidence decreased. This indicates that the aging population is the main cause of the increasing national burden associated with HF and that further attention is warranted in the management of HF in older adults.ope

Genetic Variants Associated with Adverse Events after Angiotensin-Converting Enzyme Inhibitor Use: Replication after GWAS-Based Discovery

Purpose: Angiotensin-converting enzyme inhibitors (ACEIs) are medications generally prescribed for patients with high cardiovascular risk; however, they are suboptimally used due to frequent adverse events (AEs). The present study aimed to identify and replicate the genetic variants associated with ACEI-related AEs in the Korean population. Materials and methods: A two-stage approach employing genome-wide association study (GWAS)-based discovery and replication through target sequencing was used. In total, 1300 individuals received ACEIs from 2001 to 2007; among these, 228 were selected for GWAS. An additional 336 patients were selected for replication after screening 1186 subjects treated from 2008 to 2018. Candidate genes for target sequencing were selected based on the present GWAS, previous GWASs, and data from the PharmGKB database. Furthermore, association analyses were performed between no AE and AE or cough groups after target sequencing. Results: Five genes, namely CRIM1, NELL1, CACNA1D, VOPP1, and MYBPC1, were identified near variants associated with ACEI-related AEs. During target sequencing of 34 candidate genes, six single-nucleotide polymorphisms (SNPs; rs5224, rs8176786, rs10766756, rs561868018, rs4974539, and rs10946364) were replicated for association with all ACEI-related AEs. Four of these SNPs and rs147912715 exhibited associations with ACEI-related cough, whereas four SNPs (rs5224, rs81767786, rs10766756, and rs4974539 near BDKRB2, NELL1, NELL1 intron, and CPN2, respectively) were significantly associated with both categories of AEs. Conclusion: Several variants, including novel and known variants, were successfully replicated and found to have associations with ACEI-related AEs. These results provide rare and clinically relevant information for safer use of ACEIs.ope

Phenotypic and Genetic Analyses of Korean Patients with Familial Hypercholesterolemia: Results from the KFH Registry 2020

Aims: Familial hypercholesterolemia (FH) is currently a worldwide health issue. Understanding the characteristics of patients is important for proper diagnosis and treatment. This study aimed to analyze the phenotypic and genetic features, including threshold cholesterol levels, of Korean patients with FH. Methods: A total of 296 patients enrolled in the Korean FH registry were included, according to the following criteria: low-density lipoprotein-cholesterol (LDL-C) ＞190 mg/dL with tendon xanthoma or family history compatible with FH, or LDL-C ＞225 mg/dL. DNA sequences of three FH-associated genes were obtained using whole-exome or target exome sequencing. Threshold cholesterol levels for differentiating patients with FH/pathogenic variant (PV) carriers and predictors of PVs were identified. Results: Of the 296 patients, 104 had PVs and showed more obvious clinical findings, including higher cholesterol levels. PV rates ranged from 30% to 64% when patients were categorized by possible or definite type according to the Simon Broome criteria. Frequent PV types included missense variants and copy number variations (CNVs), while the most frequent location of PVs was p.P685L in LDLR. The threshold LDL-C levels for patient differentiation and PV prediction were 177 and 225 mg/dL, respectively. Younger age, tendon xanthoma, and higher LDL-C levels were identified as independent predictors of PVs, while traditional cardiovascular risk factors were predictors of coronary artery disease. Conclusions: Korean patients with FH had variable PV rates depending on diagnostic criteria and distinctive PV locations. The reported threshold LDL-C levels pave the way for efficient patient care in this population.ope

2022 Consensus statement on the management of familial hypercholesterolemia in Korea

Familial hypercholesterolemia (FH) is the most common monogenic disorder. Due to the marked elevation of cardiovascular risk, the early detection, diagnosis, and proper management of this disorder are critical. Herein, the 2022 Korean guidance on this disease is presented. Clinical features include severely elevated low-density lipoprotein cholesterol (LDL-C) levels, tendon xanthomas, and premature coronary artery disease. Clinical diagnostic criteria include clinical findings, family history, or pathogenic mutations in the LDLR, APOB, or PCSK9. Proper suspicion of individuals with typical characteristics is essential for screening. Cascade screening is known to be the most efficient diagnostic approach. Early initiation of lipid-lowering therapy and the control of other risk factors are important. The first-line pharmacological treatment is statins, followed by ezetimibe, and PCSK9 inhibitors as required. The ideal treatment targets are 50% reduction and &lt; 70 or &lt; 55 mg/dL (in the presence of vascular disease) of LDL-C, although less strict targets are frequently used. Homozygous FH is characterized by untreated LDL-C &gt; 500 mg/dL, xanthoma since childhood, and family history. In children, the diagnosis is made with criteria, including items largely similar to those of adults. In women, lipid-lowering agents need to be discontinued before conception.ope

Genetic Variants Associated with Supernormal Coronary Arteries

Aims: Genetic and medical insights from studies on cardioprotective phenotypes aid the development of novel therapeutics. This study identified genetic variants associated with supernormal coronary arteries using genomewide association study data and the corresponding genes based on expression quantitative trait loci (eQTL). Methods: Study participants were selected from two Korean cohorts according to inclusion criteria that included males with high cardiovascular risk (Framingham risk score ≥ 14, 10-year risk ≥ 16%) but with normal coronary arteries (supernormal group) or coronary artery disease (control group). After screening 12,309 individuals, males meeting the supernormal phenotype (n??72) and age-matched controls (n??94) were enrolled. Genetic variants associated with the supernormal phenotype were identified using Firth’s logistic regression, and eQTL was used to evaluate whether the identified variants influence the expression of particular genes in human tissues. Results: Approximately 5 million autosomal variants were tested for association with the supernormal phenotype, and 10 independent loci suggestive of supernormal coronary arteries (p??5.0??10??5) were identified. The lead variants were seven intergenic single-nucleotide polymorphisms (SNPs), including one near PBX1, and three intronic SNPs, including one in PPFIA4. Of these variants or their proxies, rs9630089, rs6427989, and rs4984694 were associated with expression levels of SLIT1 and ARHGAP19, PPFIA4, and METTL26 in human tissues, respectively. These eQTL results supported their potential biological relevance. Conclusions: This study identified genetic variants and eQTL genes associated with supernormal coronary arteries. These results suggest candidate genes representing potential therapeutic targets for coronary artery disease.ope